Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

Please visit the new Evidence Based Journal Club Reviews

Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome.

The Acute Respiratory Distress Syndrome Network.

N Engl J Med 2000; 342: 1301-1308 [abstract]

Reviewed by Steven Cray Birmingham Children's Hospital, UK

Review posted April 28, 2000

---

I. What is being studied?:

The study objective:

To determine whether ventilation with lower tidal volumes would improve clinical outcomes in patients with the acute respiratory distress syndrome (ARDS).

The study design:

Multicenter randomized controlled trial

The patients included:

Patients who were intubated and receiving mechanical ventilation were eligible for the study according to the following criteria:

• an acute decrease in the PaO2/FiO2 ratio to 300
• bilateral pulmonary infiltrates on a chest radiograph consistent with the presence of edema,
• no clinical evidence of left atrial hypertension or pulmonary-capillary wedge pressure 18 mmHg

The patients excluded:

Patients were excluded according to the following criteria:

• 36 hours had elapsed since they met the entry criteria
• < 18 years of age
• participation in other trials within 30 days
• pregnant
• increased intracranial pressure
• neuromuscular disease that could impair spontaneous breathing
• sickle cell disease
• severe chronic respiratory disease
• weight > 1 kg/cm of height
• burns > 30% of body-surface area
• other conditions with an estimated 6-month mortality rate > 50%
• post- bone marrow or lung transplantation
• chronic liver disease (Child-Pugh class C)
• attending physician refused or was unwilling to agree to the use of full life support.

The interventions compared:

Traditional tidal volume group: initial tidal volume 12 ml/kg of predicted body weight (reduced stepwise by 1 ml/kg of predicted body weight if necessary to maintain plateau pressure 50 cm H2O).

Lower tidal volume group: tidal volume reduced to 6 ml/kg of predicted body weight within 4 hr after randomization (reduced stepwise by 1 ml/kg of predicted body weight if necessary to maintain plateau pressure 30 cm H2O)

The outcomes evaluated:

Primary:

• Death
• Ventilator-free days (number of days from day 1 to day 28 on which a patient breathed without assistance, if the period of unassisted breathing lasted at least 48 consecutive hours).

Secondary:

• Number of days without organ or system failure
• Barotrauma
• Plasma interleukin-6 was determined in 204 of the first 234 patients on days 0 and 3

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. A centralized interactive voice system was used for randomization.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

861 patients had been entered into the trial at the time it was stopped after the fourth interim analysis. The outcome was known for all but 9 of these patients. In addition 22 patients were still hospitalized at the time of stopping. The authors state that data on these 31 patients were censored.

Were patients analyzed in the groups to which they were randomized?

Yes. Intention to treat analysis was used.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No method of blinding was used.

4. Were the groups similar at the start of the trial?

Yes. The two groups were similar with respect to age, gender, ethnic group, APACHE III scores, number of non-pulmonary organ failures, cause of lung injury and various respiratory parameters. At study entry, minute ventilation was slightly higher in the low tidal volume group (13.4 vs. 12.7 L/min P=0.01).

5. Aside from the experimental intervention, were the groups treated equally?

Yes. The volume-assist-control mode was used for the ventilator until the patient was weaned or for 28 days after randomization. A predicted body weight was calculated for each patient on the basis of sex and height because this predicts normal lung volumes. The minimal tidal volume in both groups was 4 ml/kg of predicted body weight. Ventilator rate was adjusted from 6 to 35 breaths/min and sodium bicarbonate given if necessary to obtain a pH goal of 7.3 to 7.45. PaO2 was maintained between 55-80 mm Hg. The permitted range for inspiratory to expiratory ratio and combinations of FiO2 and PEEP were identical in the two groups.

The experimental protocol only included the management of mechanical ventilation and weaning. Other aspects of patient management in both groups were at the discretion of attending staff. The two groups did not differ with respect to muscle relaxant use and days of sedative drug administration.

The present trial was one of two trials conducted simultaneously in the same patients in a 2x2 factorial experimental design, such that ventilator strategy was evenly balanced between groups. Ketoconazole was compared with placebo in the first 234 patients (1), and lisofylline was compared with placebo in the last 194 patients; no drugs were assessed in the middle 433 patients. The authors state that these other interventions did not significantly affect the results of the present study. As reported elsewhere (1) by the authors of the present study, ketoconazole had no effect on outcome in patients with ARDS.

III. What were the results?

1. How large was the treatment effect?

Mortality was 31.0% in the group receiving lower tidal volumes and 39.8% in the group receiving conventional tidal volumes. This corresponds with point estimates for absolute risk reduction of death in the lower tidal volume group of 8.8% (95% CI of ARR 2.4% to 15.2%) and relative risk reduction of 22.1%. So, to save one life, just over 11 patients with ARDS would need to be ventilated with lower rather than conventional tidal volumes (NNT = 11.4).

Other outcome variables are shown in the table (values are mean ± SD) :

	Lower tidal volumes	Conventional tidal volumes	P value
Ventilator free days, days 1 to 28	12 ± 11	10 ± 11	0.007
Barotrauma, days 1 to 28 (%)	10	11	.43
Days free from failure of non-pulmonary organs, days 1 to 28	15 ± 11	12 ± 11	0.006

Mean plasma interleukin-6 concentrations decreased in both groups over the first 3 days of the trial, but the decrease was greater in the group receiving lower tidal volumes.

2. How precise was the estimate of the treatment effect?

For the lower tidal volume ventilation strategy, we can state with 95 % certainty that the absolute reduction in the risk of dying lies between 2.4% and 15.2% and that the number of patients needed to treat to save one life lies between 6.6 and 41.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

This trial only included adult patients and the results cannot necessarily be extrapolated to children.

2. Were all clinically important outcomes considered?

Yes, most important outcomes were included except for long-term follow-up.

3. Are the likely treatment benefits worth the potential harms and costs?

Yes. This large study in adults with ARDS showed an important reduction in mortality in those patients ventilated with lower (6 ml/kg of predicted body weight) tidal volumes. There were no harms shown and no additional costs

Reviewer's Comments

Animal studies (2) have suggested that excessive lung stretch during mechanical ventilation may contribute to the development of a systemic inflammatory response and the findings of a greater reduction in plasma IL-6 levels in the lower tidal volume group in the present study lend some support to this.

There have been a number of earlier randomized trials in patients with ARDS (3-6) which have investigated the use of "protective" ventilation strategies employing lower tidal volumes. The study of Amato (3) included 53 patients randomly assigned to ventilation with tidal volumes of 6 ml/kg or 12 ml/kg of body weight. In the lower tidal volume group peak inspiratory pressure was limited to 20 cm H2O above PEEP and hypercapnia was permitted. Mortality at 28 days was 38% in the lower tidal volmue group and 71% in the conventional-ventilation group (P < 0.001). In contrast the studies of Brochard (4), Stewart (5) and Brower (6) failed to show any improvement in mortality or other outcomes with a "protective" ventilation strategy. In Stewart's study there was a greater incidence of renal failure requiring dialysis in the group receiving lower tidal volumes.

There are a number of possible explanations for the differing results between the present study and earlier similar trials. The present study used predicted body weight rather than actual body weight to determine tidal volumes, acidosis was more actively corrected by increasing minute ventilation or the use of bicarbonate and the earlier studies may have been too small to detect moderate treatment effects. In addition, because the study was unblinded, there may have been some element of bias introduced into other aspects of patient management.

References

1. The ARDS Network Authors for the ARDS Network. Ketoconazole for Early Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial JAMA. 2000;283:1995-2002. [abstract] [full-text for a limited time]
2. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 1997;99:944-52. [abstract]
3. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347-54. [abstract] [PedsCCM EB Journal Club Review]
4. Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998;158:1831-8. [abstract] [full-text for subscribers] [PedsCCM EB Journal Club Review]
5. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 1998;338:355-61. [abstract] [PedsCCM EB Journal Club Review]
6. Brower RG, Shanholtz CB, Fessler HE, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999;27:1492-8. [abstract]

Comments

Back to the EB Journal Club Index